Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Peterson, Luke F.; Sun, Hanshi; Liu, Yihong; Potu, Harish; Kandarpa, Malathi; Ermann, Monika; Courtney, Stephen M.; Young, Matthew A.; Showalter, Hollis D.; Sun, Duxin; Jakubowiak, Andrzej; Malek, Sami N.; Talpaz, Moshe; Donato, Nicholas J.

doi:10.1182/blood-2014-10-605584

Cited by 98 publications

(105 citation statements)

References 30 publications

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“…Whether the in vitro efficacy of BA or WP + Enz (or other ADT) will replicate in animal models of CRPC is worth investigation. To begin to address the concern that BA and WP’s low solubility will have limitations for clinical use, the therapeutic value of a new orally bioavailable BA formulation and a more soluble analog of WP have been investigated in preclinical mouse models 32,60 .…”

Section: Discussionmentioning

confidence: 99%

“…The idea is that inhibiting DUBs will elevate poly-Ub on proliferation/pro-survival proteins, increase their recognition and degradation by the UPS, result in greater apoptosis, and improve drug efficacy. Several small molecule DUB inhibitors increase accumulation of poly-Ub proteins and result in greater apoptosis in cancer cells 27–32 . Currently, DUB inhibitors are in the preclinical stage of research and no results from clinical trials are yet known.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells

Pozas

Reiner

Cesare

et al. 2018

Sci Rep

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Prostate cancer (PCa), a leading cause of cancer-related death in men, becomes resistant to androgen deprivation therapy by inducing androgen receptor (AR) activity, which is known as castration-resistant PCa (CRPC). Enzalutamide is an approved drug that inhibits AR activity and increases overall survival. However, resistance to enzalutamide develops rapidly often by increasing AR activity, suggesting that new therapies are required for CRPC. We investigated whether betulinic acid (BA), a small molecule from plants that inhibits multiple deubiquitinases (DUBs), reduces AR, and selectively kills PCa cells, can provide an adjuvant strategy for CRPC. Our data indicated that BA reduced AR protein stability and mRNA expression, making it an attractive agent for CRPC. BA decreased AR mRNA possibly by inhibiting a histone 2A DUB thereby increasing ubiquitinated histone 2A, a transcriptional repressor. We identified multiple and specific DUBs inhibited by BA either in PCa cells or using recombinant DUBs. Similar results were obtained using another multi-DUB inhibitor WP1130, suggesting that these DUB inhibitors can decrease AR expression and increase PCa-specific death. Our results also suggest that combining multi-DUB inhibitors BA or WP1130 with enzalutamide may provide a novel strategy for CRPC by further decreasing AR expression and increasing apoptotic cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells

Pozas

Reiner

Cesare

et al. 2018

Sci Rep

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“…USPs can release poly-Ub chains from proteins targeted for degradation, recycle monomeric Ub, liberate Ub from Ub-fusion precursors, reverse regulatory ubiquitylation and edit inappropriately ubiquitylated proteins [4–5]. USPs, such as USP1 [6], USP2 [7], USP7 [8], USP9x [9] and USP14 [10], were recently shown to contribute to the development of cancer and are emerging as novel cancer drug targets [11–12]. USP7, also known as herpes-associated USP, has been found to be critical in cancer progression because of its influence on the stability of the tumor suppressor p53 [13].…”

Section: Introductionmentioning

confidence: 99%

CDDO-Me reveals USP7 as a novel target in ovarian cancer cells

Qin

Wang

et al. 2016

Oncotarget

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Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation.

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“…WP1130 was also found to activate Bcr/Abl destruction and induce apoptosis of CML cell lines as well as for its potential use in B-cell malignancies [122]. It was recently found to block autophagy and is currently in preclinical development and awaiting entry into clinical trials [122,123]. Proteasomal-dependent degradation of c-Myc is also activated by WP1130 in MM and other tumor cell lines using signaling processing domains not previously associated with c-Myc regulation [124].…”

Section: Dub Inhibitorsmentioning

confidence: 99%

“…WP1130 (degrasyn) was derived from a Janus-activated kinase (JAK2) inhibitor called AG490, and has been shown to be active towards at least five DUBs including USP9x, USP5, USP14 and UCH-L1 [73]. WP1130 was also found to activate Bcr/Abl destruction and induce apoptosis of CML cell lines as well as for its potential use in B-cell malignancies [122]. It was recently found to block autophagy and is currently in preclinical development and awaiting entry into clinical trials [122,123].…”

Section: Dub Inhibitorsmentioning

confidence: 99%

Targeting Ubiquitination for Cancer Therapies

Morrow¹,

Lin

Sun

et al. 2015

Future Med. Chem.

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Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system. Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the ubiquitin-proteasome system is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family.Ubiquitination, a step in the nonlysosomal degradation of proteins, is a crucial post-translational modification in eukaryotic organisms. Rapid and timely degradation of transcriptional regulators and other proteins by the ubiquitin-proteasome system (UPS) regulates a wide variety of cellular processes [1]. Ubiquitination involves covalent attachment of ubiquitin, a small 8-kDa protein, to a substrate and results in recognition and shuttling of the substrate to the 26S proteasome complex for degradation [2]. It is important to note that the ubiquitination process combined with the proteasome complex step is also referred to as the ubiquitin-proteasome system (UPS) or ubiquitin proteasome pathway (UPP).The ubiquitination process is tightly controlled by three families of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and finally ubiquitin-protein enzymes (E3s). There exists two E1 enzymes with ubiquitin-activating capability: UBA1 being the primary E1 and the recently discovered UBA6 with unclear functions and uncharacterized regulations [3,4]. In contrast to the small number of E1s, there are approximately 40 E2s [5,6] and 500-1000 human E3 ligases, providing both specificity and versatility [7]. The three steps of the ubiquitination process (Figure 1) have been reviewed previously [8,9]. Briefly, the activation step requires binding of both ATP and ubiquitin and links the α-carboxyl group of the C-terminal glycine residue of ubiquitin to a cysteine residue on E1, and a thioester linkage is formed between the u biquitin and E1.Then the E2 binds to both activated ubiquitin and the E1 enzyme and thus transfers the ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. Finally, the E3 catalyzes the linking of ubiquitin to a lysine residue on the substrate. Repetitions of these sequential steps results in a long chains of ubiquitin (polyubiquitin) on the protein to be degraded, and the specific lysine residue on ubiquitin used for linking (e.g., K48, K63, etc.) results in different topologies [10]. Ubiquitination was originally described as a mechanism by which cells dispose of short-lived, damaged, or abnormal proteins, but more rece...

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Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Abstract: Key Points Deubiquitinases Usp9x and Usp24 regulate Mcl-1 and myeloma cell survival. Small-molecule–mediated Usp9x/Usp24 inhibition induces apoptosis and blocks myeloma tumor growth in vivo.

Cited by 98 publications

References 30 publications

Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells

Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells

CDDO-Me reveals USP7 as a novel target in ovarian cancer cells

Targeting Ubiquitination for Cancer Therapies

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